This invention relates generally to plural-substituted pyridine derivatives and, particularly, to processes for preparing and isolating 2-chloro-5-trifluoromethylpyridine and using same.
Although a large number of functionally substituted pyridine compounds are known and capable of synthesis, certain patterns of disubstitution, in particular, on the pyridine ring are difficult to obtain by any convenient and commercially viable means. Pyridines having functional substituents in the 2- and 5- positions on the ring are often valuable derivatives, but fall within this category. For example, hydroxyl, cyano, carboxy, chloro and other groups are difficult to introduce into these positions on the pyridine ring.
One 2- and 5- disubstituted pyridine compound gaining in commercial interest in recent years is 2-chloro-5-trifluoromethylpyridine. It appears from the prior art that the compound would be useful as a plant growth regulator and useful for the suppression of nitrification of ammonia in the soil. Additional areas of use can be determined from U.S. Pat. Nos. 3,609,158 and 3,705,170. Still further, it has proven an important intermediate reaction product in the preparation of herbicides and for polymer modification.
Nevertheless, only three methods of synthesis for this pyridine compound have been reported, none of which have proven to be of particular commercial value. These known methods will be specifically described below following a background discussion of the synthesis reaction in general.
First, as to the trifluoromethyl substitution, it is generally known that alkyl and aromatic carboxylic acids react with sulfur tetrafluoride in the presence of hydrogen fluoride to give trifluoromethyl derivatives. Boswell et al., Org. Reactions, 21, 30 (1974). This reaction is known to take place in two steps as represented below. ##STR1## The first step is the facile conversion of the carboxylic acid to an acid fluoride which occurs at low temperatures. The second step is not as facile, but requires more vigorous conditions. The hydrofluoric acid both added and generated in the first step combine to act as a catalyst in the final trifluoromethyl formation. Although these steps are distinct, the reaction generally proceeds without isolation of the acid fluoride, with the initial reaction mixture simply being heated to convert the intermediate acid fluoride to the final trifluoromethyl group. Boswell et al., supra.
This trifluoromethylating reaction has been applied to various compounds including amino acids, simple pyridine carboxylic acids such as niacin and 3,5-dicarboxypyridine. Kobayashi et al., Chem. Pharm. Bull., 15, 1896 (1967); Raasch, J. Org. Chem., 27, 1406 (1962). It has also been applied to esters and anhydrides of these carboxylic acids to give the corresponding fluorinated ethers, the double-bonded oxygen functions being simply replaced during the fluorination reaction. Hasek, Smith, & Engelhardt, J. Amer. Chem. Soc., 82, 543 (1960). ##STR2##
It is also known that this final trifluoromethylating step proceeds equally well when an acid chloride compound is used instead of the intermediate acid fluoride. ##STR3## However, the reaction product is not always straightforward as in the following example where an unexpected chlorination resulted. ##STR4##
As to chlorine substitution in general, the standard method of acid chloride preparation is the reaction of a carboxylic acid with an agent such as phosphorus pentachloride, phosphorus oxychloride, or a combination of the two, or with a thionylchloride in the presence of a solvent such as dimethylformamide. J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 346-347 (1968). ##STR5## Similarly, 2- and 4-hydroxypyridines, also called pyridones, are known to readily convert to their 2- and 4-chlorine derivatives by reaction with these same reagents. Klingsburg, Pyridine and Its Derivatives, Part Three, 646 (1962). Abramovitch, Pyridine and Its Derivatives, 785, 790-791 (1974). 3-Hydroxypyridines are not affected by such reagents.
However, the presence of a hydroxy group is known to lead to undesirable reactions involving this additional oxygen function in the trifluoromethylation reaction. In particular, 2- and 4-hydroxypyridines have been shown to physically exist as a mixture of tautomeric forms, appearing both as the hydroxy and as the amide derivatives. R. Elderfield, Heterocyclic Compounds, 1, 435-440 (1950). ##STR6## For this reason, these hydroxypyridines undergo reactions typical of both phenols and amides as also reported in the Elderfield reference. ##STR7## Similar behavior has been reported in substituted hydroxypyridines such as the 5-carboxy-2-hydroxypyridines, also known as 5-carboxy-2-pyridones in their alternate form. Klingsberg, Pyridine and Its Derivatives, Part Three, 646 (1962).
It is known that hydroxy groups give rise to fluoro groups by standard substitution upon treatment with sulfur tetrafluoride. Sharts & Sheppard, Org. Reactions, 21, 125 (1973). It is also known that amides react with sulfur tetrafluoride to give a variety of products. Hasel, Smith & Englehart, J. Amer. Chem. Soc., 82, 543 (1966). For example, if the amide contains at least one nitrogen-hydrogen bond, cleavage at the nitrogen-carbon bond is reported to occur. ##STR8##
With this background, there are three reported methods for synthesis of this disubstituted 2-chloro-5-trifluoromethylpyridine.
The first reference is U.S. Pat. No. 2,516,402, issued on July 25, 1950 to McBee et al. This patent claims various new fluoromethylpyridines which were prepared by the chlorination of methylpyridines, in which complete substitution took place on the side-chain and to some extent on the ring as well. McBee et al. report that this chlorination on the pyridine ring, which is ordinarily difficult to accomplish, appears to be aided by the presence of one or more trichloromethyl groups on the ring. Fluorination of these side-chains was then accomplished with hydrogen fluoride.
A second reported synthesis is apparently disclosed in an abandoned U.S. Pat. application, Ser. No. 749,977 originally filed Aug. 5, 1968 and assigned to Dow Chemical Company of Midland, Michigan. The content of this abandoned application is not presently known, but it is believed to produce the trifluoromethyl-chloro derivative by standard halogen substitution from the trichloromethyl-chloro compound similar to the McBee et al. patent. This belief is based upon references in two later Dow patents, U.S. Pat. Nos. 3,705,170 and 3,609,158, to this abandoned application. Specifically, each patent cross-references this application and only generally discusses the preparation of its starting materials beginning at col. 20, l. 42 in Dow U.S. Pat. No. 3,705,170 and at col. 19, l. 49 in Dow U.S. Pat. No. 3,609,580.
A final synthesis of 2-chloro-5-trifluoromethylpyridine is reported in U.S. Pat. No. 4,038,396 issued to Shen et al. on July 26, 1977. The following series of reactions were disclosed in Example 111 of this patent beginning at column 23, line 62. ##STR9##
As seen in this representation, Shen et al. first teaches the chlorination of 6-hydroxynicotinic acid, also known as 5-carboxy-2-hydroxypyridine and 5-carboxy-2-pyridone, obtaining 2-chloro-5-carboxypyridine as the reaction product. As previously discussed, this chlorination actually involves two distinct steps, the acid chloride group being hydrolyzed back to the carboxylic acid when cooled in crushed ice prior to filtration. The 6-chloronicotinic acid intermediate is then subjected to standard trifluoromethylation using sulfur tetrafluoride in the presence of hydrogen fluoride also as previously described.
These three known methods are lengthy and complex, and are not known to be commercially significant. They further point to the need for the development of a viable, more efficient method for preparing this commercially valuable compound.